OVERVIEW: What every practitioner needs to know

Treacher-Collins syndrome (TCS, also known as mandibulofacial dysostosis or Franceschetti-Zwahlen-Klein syndrome) is an autosomal dominant condition that typically results from a spontaneous mutation in the gene TCOF1, which encodes a nucleolar phosphoprotein named Treacle. TCS results in symmetric craniofacial defects, the severity of which varies considerably from person to person and generation to generation. Deformities in TCS are confined to the head and neck. No correlation exists between genotype and phenotype. Patients with TCS generally show normal intelligence but frequently have conductive hearing loss. Therefore, providers should identify and correct any underlying hearing problems to maximize the development of these patients. Initial treatment is aimed at ensuring that the airway is secure.

Are you sure your patient has TCS? What are the typical findings for this disease?

TCS generally results in the following symmetric craniofacial deformities:

Lateral downward sloping palpebral fissures (89%)

Zygomatic hypoplasia (81%)

Mandibular hypoplasia (78%)

External ear abnormalities (77%)

Colobomas (69%)

Absence of lid lashes medial to defect (69%)

External auditory canal atresia (36%)

Cleft palate (28%)

Genetic analysis identifies mutations in the TCOF1 gene in 90% of patients. Over 130 different mutations have been identified in the TCOF1 gene, requiring full gene sequencing to make the diagnosis.

What other disease/condition shares some of these symptoms?

Other conditions with craniofacial defects:

Hemifacial Microsomia

Pierre Robin Sequence

Nager Syndrome

Miller Syndrome

Binder Syndrome

Velocardiofacial Syndrome

Stickler and Marshall Syndromes

Van Der Woude Syndrome

What caused this disease to develop at this time?

TCS is present at birth due to failure of the 1st and 2nd branchial arches to develop properly in utero. Greater than 90% of cases of TCS are the result of an autosomal dominant mutation on the TCOF1 gene, which encodes the protein Treacle, and which has been shown to be critical in ribosome biogenesis. Given the autosomal dominant inheritance pattern, children of affected individuals have a 50% probability of inheriting the mutation; however, the majority (60%) of patients with TCS have de novo gene mutations.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Historically, TCS was a clinical diagnosis. Now, genetic analysis of the gene TCOF1 will detect mutations in 90% of patients; thus, the presence of appropriate deformities with a mutation in TCOF1 is sufficient for a diagnosis of TCS.

Between 7%-20% of patients will have no mutations identified in TCOF1 despite a classic TCS phenotype. In these patients, a TCS diagnosis can be made if other craniofacial syndromes are excluded. Research published in 2011 identified the presence of mutations in other ribosomal related genes (POLR1C & POLR1D) in TCS patients without identifiable mutations in TCOF1.

Confirming the diagnosis

Trainor et al. put forth a diagnostic algorithm (Figure 1). In their algorithm, confirmation of TCS by mutational analysis of TCOF1 requires management by a comprehensive team consisting of a craniofacial surgeon, orthodontist, ophthalmologist, otolaryngologist, and speech pathologist. Absence of a TCOF1 mutation prompts a search for an alternative diagnosis (i.e., Nager Syndrome);

Use caution, as a subset of patients with phenotypic TCS (7%-20%) will have no mutations identified in TCOF1.

If you are able to confirm that the patient has TCS, what treatment should be initiated?

A multidisciplinary approach towards patients with TCS is required and should include craniofacial surgeons, otolaryngologists, orthodontists, ophthalmologists, speech pathologists, and geneticists.

Immediate: Initial management should emphasis the airway, as patients with severe micrognathia and subsequent obstruction of the hypopharynx may require tracheostomy or measures such as long-term placement of a nasopharyngeal airway to secure their airway.

May consider earlier if sleep apnea is a major issue and the child does not have a tracheostomy tube placed.

External/internal ear reconstruction (age 6 years)

What are the possible outcomes of TCS?

While the majority of new cases of TCS are caused by spontaneous mutations in TCOF1, patients with TCS have a 50% chance of having children with TCS. Patients should be counseled that the severity of the disease has dramatic variability between generations and siblings.

Because of the high degree of phenotypic variation, there are case reports of parents with subtle deformities being diagnosed with TCS only after having children who present with more severe deformities. Parents of a child affected with TCS should have an evaluation and genetic counseling for TCS, especially if they are considering have additional children.

Typically, patients will require multiple surgeries and never attain "normal" cosmesis. In a study of 50 patients with TCS, the average patient underwent 5.2 operations.

What causes this disease and how frequent is it?

Epidemiology

Worldwide incidence: 1 in 25,000 - 50,000 live births

60% of cases occur spontaneously

Molecular Genetics

TCOF1

Located on chromosome 5 (5q31.3-q33.3)

Encodes the nucleolar phosphoprotein, Treacle, which is highly expressed in neural crest cells of the brachial arches

Treacle is essential in ribosomal RNA transcription and ribosome biogenesis.

90% of patients have a mutation in the gene TCOF1

>130 mutations in TCOF1 have been identified

Defects have variable penetrance. No correlation between specific mutations and clinical severity has been established.

POLR1D

Located on chromosome 13

Encodes subunit of RNA polymerase I and III

~8% of patients negative for TCOF1 have mutations in POLR1D

Supports hypothesis that TCS is a ribosomopathy

How do these pathogens/genes/exposures cause the disease?

Currently, there is no evidence that pathogens or exposures
in utero can cause TCS. While ongoing studies are elucidating the mechanisms by which TCS causes deformities, it is generally agreed that TCS is the result of an abnormality of the neuroepithelium of the first and second branchial arches. Previously, the phenotype was thought to be a consequence of decreased neural crest cell migration; however, new studies implicate increased apoptosis and decreased proliferation of neuroepithelial cells.

TCOF1 gene mutations were thought to be necessary to develop TCS, but a recent subset of patients who phenotypically have TCS without a TCOF1 mutation have been identified. Eight percent of these patients were found to have mutations in POLR1C or POLR1D.

Other clinical manifestations that might help with diagnosis and management

Prenatal diagnosis with amniocentesis, chorionic villus sampling or ultrasound are possible to detect mutations in TCOF1. Due to the high degree of variability of the TCS phenotype, decisions regarding testing and management are difficult and should be discussed with a geneticist.

Other clinical considerations for airway management

While watchful waiting is an appropriate option for the initial airway management in a newborn with TCS and mild airway compromise, frequently additional interventions are required because of frank respiratory distress, failure to thrive, or obstructive sleep apnea (OSA). Evaluation of airway compromise can involve the use of polysomnography and feeding evaluation. Management options include:

Long-term nasopharyngeal airway - While studies are limited in the use of long-term nasopharnygeal airway (NPA) in TCS, in a study of patients with syndromic craniosynostosis, NPA was preferred by parents over tracheostomy and reduced, but did not always completely ameliorate, the severity of OSA.

Tracheostomy - In one series, ~40% of TCS patients eventually underwent tracheostomy. While tracheostomy can definitively alleviate upper airway obstructions, it is associated with increased rates of tracheal stenosis, granulomas, and other complications.

Distraction osteogenesis (DO) - Involves making a cut in the maxilla or mandible or both, and applying tension to separate the bone, thus allowing new bone formation in between the cut ends. DO is indicated for infants and children with OSA secondary to micrognathia or midface hypoplasia.

Other management strategies, including positive airway pressure and oxygen therapy, as discussed in the OSA section.

Respiratory compromise in TCS is not limited to the neonatal period. OSA is present in the majority of pediatric and adult TCS patients with no correlation between the severity of TCS and the severity of OSA. While there is no consensus on the timing and frequency for polysomnography, given the morbidity and mortality associated with OSA and the high prevalence of OSA in TCS patients, screening for OSA should be considered early.

How can TCS be prevented?

While TCS is an autosomal dominant disease, the majority of patients with TCS have mutations that occur spontaneously. Patients who might wish to have children should be referred for genetic counseling, because they have a 50% chance of passing on this condition to their offspring.

There is no current method for preventing new mutations. Mouse models have validated the role of pharmacologic and genetic inhibition of tumor suppressor p53 to prevent TCS; however, this is not currently a viable preventative strategy because the insult occurs early in embryological development, and perturbation with p53 results in tumor formation.

(While there are no studies looking at the use of a nasopharyngeal airway (NPA) for obstructive sleep apnea (OSA) on patients with TCS, this article does demonstrate that the NPAs can help reduce the severity of OSA for patients with other craniofacial syndromes.)